Alphaviruses, such as Chickungunya and Ross River virus (RRV), are a significant cause of disease worldwide. Though the pathogenesis of alphavirus-induced arthritides is poorly understood, viral interactions with the innate immune system likely contribute to disease. Therefore, we propose to characterize the role of innate inflammatory mediators, such as cytokines, chemokines, and pattern recognition receptors, in a mouse model of RRV-induced inflammation. We propose the following specific aims. 1) Characterize the inflammatory cytokine and chemokine response to RRV infection in vivo and in vitro. 2) Determine the role of IFN-gamma in RRV-induced disease. IFN-y-deficient mice, which unlike wild-type mice do not develop severe disease, will be used to investigate IFN-gamma's role in RRV pathogenesis. Cellular sources of IFN-gamma in RRV-infected mice will be investigated. 3) Investigate the role of pattern recognition receptors in RRV-induced inflammatory and immune responses. Toll-like receptors and the CARD-containing RNA helicase RIG-1 will be evaluated for their role in recognizing Ross River virus infection in vitro using transfection systems and RNAi technology. Additional studies will elucidate viral components that elicit inflammatory responses.